What is PGT and PGT-SR?
Pre-implantation Genetic Testing (PGT), previously known as Pre-implantation Genetic Diagnosis (PGD), is a technique used alongside IVF by couples who have a particular inherited condition to avoid passing it on to their children. Pre-implantation Genetic Testing for Chromosomal Structural Rearrangements (PGT-SR) is used when either one of the couple is known to have a chromosomal structural abnormality. The technique allows embryos created through IVF to be tested in order to find out if they have inherited the chromosomal abnormality so that an unaffected embryo can be transferred to the womb and hopefully will result in the birth of an unaffected baby.
What is a chromosomal rearrangement?
A chromosomal rearrangement is a type of chromosomal abnormality involving a change in the structure of the native chromosome(s), which can be translocations, inversions or other complex changes. These events are caused by two breakages in one or two chromosome(s), followed by an exchange and then a rejoining of the broken ends to produce a new chromosomal arrangement.
Carriers of these chromosomal rearrangements are usually healthy, but they may produce sperms or eggs and hence subsequently embryos with an incorrect number of the whole or a segment of the chromosomes, i.e. unbalanced chromosomal translocations.
Embryos with unbalanced translocations may grow at a normal rate in their early stages and look like the same as normal embryos. It is therefore possible to select an embryo for transfer that looks normal but actually contains an unbalanced translocation. This embryo will most likely fail to implant in the womb or miscarry during early pregnancy. However, sometimes a pregnancy can reach full term and an unhealthy baby is born with an unbalanced chromosomal translocation. PGT-SR can be used to check if an embryo has an unbalanced translocation so as to avoid transferring this embryo. Sometimes it is even possible to distinguish a normal embryo from an embryo with a balanced translocation. An embryo with a balanced translocation contains the correct number of genetic materials. It can grow to become a healthy person but will have the same problem that his / her parents are now facing when he / she plans to start his / her family. Therefore, if there is no normal embryo available, transferring an embryo with a balanced translocation can be considered.
What does PGT-SR involve?
After discussing with your doctor regarding the PGT-SR test, you may be referred to see a genetic counsellor who will discuss with you your specific condition, especially if your chromosomal rearrangement condition is a rare one. If you wish to proceed with PGT-SR, you will need to see your doctor again to sign the consent forms for IVF and PGT-SR. Your doctor will then arrange with HKARC, the IVF centre, and the PGT laboratory at the University of Hong Kong to develop your specific PGT-SR test. This may take 2 to 6 weeks depending on the complexity of the condition. When the PGT laboratory confirms with your doctor that your PGT-SR test is ready, then you can start the IVF treatment in the following cycle.
The first step of PGT-SR is to go through an IVF treatment cycle. During the IVF cycle, each egg is fertilized with a sperm using intracytoplasmic sperm injection (ICSI) to avoid redundant sperms sticking to the outer sheath of the egg which will interfere with the test result.
The embryos are cultured for five days, or sometimes six days, until they become blastocysts. Those embryos that can grow to become good quality blastocysts are biopsied whereby a few trophoectoderm (TE) cells are removed from the blastocyst. These cells are “extra-embryonic” and will produce tissues such as the placenta. The inner cell mass (ICM) is the group of cells that will become the baby. There are over 100 trophoectoderm cells in a blastocyst so the removal of a few of these cells will have minimal impact on the embryo. Straight after the biopsy procedure the embryos are frozen to await the result of the test. The cells removed by biopsy are analysed at the PGT laboratory at the University of Hong Kong. The test report normally takes around 3 weeks, when a frozen-thawed embryo transfer (FET) can be arranged in the following cycle if there are suitable embryos for transfer.
Do we have any alternatives to PGT-SR?
If you do not have fertility problems, you can choose to conceive naturally and then consider prenatal testing by chorionic villous sampling or amniocentesis. For most couples this route actually gives them the highest chance of having a healthy baby. However, it does mean that the couple may be faced with the very difficult decision about whether to continue or to terminate an affected pregnancy. Some couples consider other options including use of donor eggs or sperms, adoption, or not having children.
What are the potential problems or risks of PGT-SR?
1) Risks of the cell biopsy procedure: It is not yet known whether embryos that have been biopsied have the same chance of implanting as embryos that have not been biopsied. In other words, the biopsy procedure itself may reduce the chance of the embryo implanting. Babies born from IVF with PGT do not have any more birth defects than occur naturally in the general population.
2) Possibility of having no unaffected embryo for transfer: During the process of embryo culture, there is a chance that no embryo can grow to become blastocyst and therefore there is no embryo for biopsy; or the PGT-SR test may find that none of the embryos are normal or with a balanced translocation, i.e. unaffected. In both these situations, there will be no embryo for transfer. The likelihood that either of these happening is influenced by a variety of factors, the most significant ones are advancing female age and women with low ovarian reserve and thus having a small number of embryos to work with.
3) Risk of having a false negative or a false positive test result: No test is perfect. There is a chance of the test reporting an affected embryo as unaffected, i.e. a false negative result. The consequence is that the embryo will most likely fail to implant or may miscarry, or may result in the birth of an affected baby. It is for this reason that even if you conceive after PGT-SR, prenatal testing during pregnancy is still recommended to ensure that the baby is healthy. On the contrary, there is a chance of the test reporting an unaffected embryo as affected, i.e. a false positive result. The consequence is that an unaffected embryo is not transferred when it could have led to the birth of a healthy baby. The chance of the PGT-SR test having a misdiagnosis is ~5%.
4) Risk of the test yielding no result: A no result or inconclusive result sometimes happens (<5%). These situations arise because some biopsied cells do not contain any genetic material, or sometimes cells may be lost during the complicated fixation process, or may have suboptimal fixation meaning they cannot be used for analysis.
5) PGT-SR does not test for chromosomal aneuploidy: PGT-SR tests for a specific chromosomal rearrangement only. It does NOT test whether the embryo has a correct number of chromosomes. The risk of having an embryo affected by a chromosomal aneuploidy (extra or missing chromosomes) is influenced by the age of the women. The older the woman is, the higher the chance of having a pregnancy with an incorrect number of chromosomes (aneuploidy). This is separate from the problem of chromosomal rearrangement that one of the partners carries, which has no association with the woman’s age. An aneuploid embryo will fail to implant mostly, or miscarry in early pregnancy. Occasionally, it may grow to term and may result in a baby with birth defects. Pre-implantation Genetic Testing for Aneuploidies (PGT-A) is a test to check if the embryo has a correct number of chromosomes. It is possible to perform both PGT-SR and PGT-A tests simultaneously with the same biopsied cells.
6) PGT-SR does not screen for or detect any genetic disorders: PGT-SR does NOT and CANNOT detect any genetic disorders such as Thalassaemia. If either one or both partners carry a specific genetic disorder that could impair the normal development of a child affected by the disorder, the couple should consider Pre-implantation Genetic Testing for Monogenic / Single Gene Disorders (PGT-M).
